Double-responsive hyaluronic acid-based prodrugs for efficient tumour targeting

Hyaluronic acid (HA)-based prodrugs bearing double-responsive (acid pH or oxidation) boronates of catechol-containing drugs were used to treat xenografted human prostate tumours (LNCaP) in SCID mice. The HA prodrugs accumulated significantly only in tumours (impressively, up to 40% of the injected dose after 24 h) and in liver, with negligible – actually anti-inflammatory - consequences in the latter. A quercetin-HA prodrug significantly slowed down tumour growth, in a dose-dependent fashion and with a much higher efficacy (up to 4 times) than equivalent doses of free quercetin. In short, boronated HA appears to be a very promising platform for targeted chemotherapy. Hyaluronic acid-based prodrugs bearing side-chain boronic esters show excellent tumour accumulation (targeting) and acid pH- or reactive oxygen species (ROS)-responsive release of polyphenolic drugs such as quercetin. The chemotherapeutic performance of the latter in xenografted mice is dramatically improved upon conjugation with HA. [Display omitted] •Boronate-linked payloads can be released from hyaluronic acid upon acidification or oxidation.•Boronate-based hyaluronic acid prodrugs accumulate in tumours up to 40–50% of the injected doses.•Boronate-based hyaluronic acid prodrugs efficiently treat human prostate tumours in SCID mice.